Stroke is the third leading cause of death in industrialized countries and a leading cause of acquired disability in adults. Each year, about 700,000 people experience stroke in the United States. Ischemic stroke constitutes about 85% of all strokes. Ischemic stroke is a complex genetic disorder, the result of interactions between multiple genes and multiple environmental exposures. Several epidemiological lines of evidence suggest an important genetic component to the overall risk of acquiring stroke. Cohort studies show that a positive family history for stroke increases stroke risk by 30%. The affected sibling pair methodology has been used successfully in other neurological and non-neurological disorders to define risk factor loci and has lead to the discovery of novel risk factor genes that would not have been assumed a priority to be key to the pathogenesis of these disorders. The affected sibling pair approach to risk factor locus discovery should be applied to ischemic stroke. The broad long-term objective of the application is to search for regions of interest in the human genome that may harbor stroke susceptibility genes. This is a competing continuation of the multicenter Siblings With Ischemic Stroke Study (SWISS). As of October 2004, DMA samples have been obtained from 170 affected sibling pairs (174 probands and 240 full siblings). The primary aims are: (1) to collect DMA samples from 300 sibling pairs concordant for ischemic stroke and 200 siblings discordant for ischemic stroke (total number of study subjects = 800), and (2) to perform a genome-wide screen for genetic risk factors for ischemic stroke using microsatellite markers spaced at 20 centimorgan intervals. Secondary aims include the identification of genetic regions of interest associated with ischemic stroke in adults below the age of 50 years and the identification of genetic regions of interest that are independent of the status of diabetes, hypertension, cigarette smoking, and atrial fibrillation among study subjects. Probands will be screened from patients who present with acute ischemic stroke to 1 of about 50 centers. A centralized stroke verification committee will assure accuracy in phenotyping. Ischemic strokes are classified in all affected individuals using the Trial of ORG10172 Acute Stroke Treatment (TOAST) criteria. DNA banking and the creation of permanent lymphoblastoid cell lines will be done to permit future collaborative efforts to study the genetic basis for stroke risk.